O H NH 2 Cl N H O H Me H H Me Me Me OTBS OTBS Me Me OTBS OTBS Pd-RuPhos RuPhos NaOt-Bu, PhMe
125 °C, 24 h 5.18 5.22 5.27 Br O H Cl N O H Me H H Me Me Me OTBDPS OTBDPS Me Me OTBDPS OTBDPS Palladium Source Ligand
NaOt-Bu, Solvent 125 °C NH TIPSO TESO TIPSO TESO Br O H NH 2 Cl N H O H Me H H Me Me Me OTBDPS OTBDPS Me Me OTBDPS OTBDPS Palladium Source Ligand
NaOt-Bu, Solvent 125 °C 5.18 5.9 5.25 5.25 5.26 5.27
Also, one of the major drawbacks of the current optimized conditions employing in the estrone model eastern hemisphere, is that two equivalents of the eastern hemisphere are required and that 40 mol % palladium is necessary to drive the reaction to completion. Optimized reaction conditions for the model eastern hemisphere unfortunately do not appear to translate well to the real nodulisporic acid D system. In order to determine the optimal conditions for the real system, the Merck screening facility at the University of Pennsylvania should be employed in the future. Chloroaniline 5.18 could be used as the western hemisphere in such screens. Reactions of vinyl bromides such as 5.22 possessing bis-TBS protected hydroxyls however may be difficult to follow by HPLC or LC/MS as no chromophore is present: moreover this system appears not to undergo ready ionization during LC/MS analyses. It would thus appear advisable to exchange the TBS groups with tert-butyl diphenyl silyl groups such as in 5.25. Hopefully, this minor change would not affect the reactivity of the various advanced intermediates in any significant manner, but would incorporate a chromophore that would make the analysis of the catalyst screen more facile. This same approach could also be taken to optimize conditions for nodulisporic acid A. Moreover, the Merck resource would provide access to a wider variety of catalysts, ligands, and conditions, while using less precious late-stage material.
5.5. REFERNCES FOR CHAPTER 5
!
1. (a) Gonzales, S. Synthetic Studies Of (+)-Nodulisporic Acid A: Development Of An Efficient Route To Eastern Hemisphere Sub-Targets. University of Pennsylvanita, 2011; (b) Jeon, J., Unpublished Results. University of Pennsylvania: 2012.
2. Biscoe, M. R.; Fors, B. P.; Buchwald, S. L., A New Class of Easily Activated Palladium Precatalysts for Facile C−N Cross-Coupling Reactions and the Low
Temperature Oxidative Addition of Aryl Chlorides. J.Am. Chem. Soc. 2008, 130 (21), 6686-6687.
3. Chakravarty, P. K.; Shih, T. L.; Colletti, S. L.; Ayer, M. B.; Snedden, C.; Kuo, H.;
Tyagarajan, S.; Gregory, L.; Zakson-Aiken, M.; Shoop, W. L.; Schmatz, D. M.; Wyvratt, M.; Fisher, M. H.; Meinke, P. T., Nodulisporic acid side-Chain modifications: access to
the 2'', 3'', 4'', and 6'' registers. Bioorg. Med. Chem. Lett. 2003, 13 (1), 147-150.
4. Knapp, J. M.; Zhu, J. S.; Tantillo, D. J.; Kurth, M. J., Multicomponent Assembly of
Highly Substituted Indoles by Dual Palladium-Catalyzed Coupling Reactions. Ang.
Chem. Int. Ed. 2012, 51 (42), 10588-10591.
! ! !
6.1 MATERIALS AND METHODS
All solvents used were reagent grade. Diethyl ether (Et2O), tetrahydrofuran (THF),
methylene chloride, and toluene were obtained from a PurSolv™ PS-400. All reagents were purchased from Aldrich or Acros and used as received. Reactions were magnetically stirred in oven-dried glassware under an argon atmosphere and monitored by thin layer chromatography (TLC) with 0.25 mm E. Merck pre-coated silica gel plates. All starting materials were azeotroped with benzene (3x) and dried under vacuum prior to use. Flash chromatography was performed with silica gel 60 (particle size 0.040 – 0.062 mm) supplied by Silicycle and Sorbent Technologies. MPLC refers to medium pressure liquid chromatography (25-200 psi) using hand-packed columns of Silasorb silica gel (18-32 µm, 60 Å pore size), a Waters HPLC pump, a Waters R401 differential refractive index detector, and a Gilson 116 UV detector. Yields refer to chromatographically and spectroscopically pure compounds, unless otherwise stated. Infrared spectra were recorded on a Jasco Model FT/IR-480 Plus spectrometer. Proton and carbon NMR spectra were recorded on a Bruker AMX-500 and Bruker Avance III 500 MHz spectrometer. Chemical shifts are reported relative to either chloroform (δ 7.27) or benzene (δ 7.16) for 1H NMR and either chloroform (δ 77.16) or benzene (δ
128.4) for 13C NMR. Optical rotations were measured on a Perkin-Elmer model 241
polarimeter or a Jasco polarimeter. High resolution mass spectra were measured at the University of Pennsylvania Mass Spectrometry Service Center.
!
88!
Bromomethylbenzoate 2.11:
Commercially available methyl benzoate (100 mL, 771 mmol) in a sealed tube was dissolved in MeCN (100 mL, 7.71 M). NBS (106.9 g, 600 mmol, 0.778 equiv) and FeCl3 (48.7 g, 300 mmol, 0.389 equiv) were added to the solution and the sealed tube was closed. The reaction mixture was warmed to 110 °C and stirred for 48 h. The reaction mixture was quenched with saturated aqueous Na2S2O3 and extracted with Et2O. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The starting material, methyl benzoate was first distilled under a reduced pressure (bp 58 °C / ca. 10 torr) as a clear colorless oil (37 g, 35 %) and the product 2.11 was distilled under a reduced pressure (bp 120 °C / ca. 10 torr) as a clear colorless oil (106 g, 64 %). 1H NMR (500 MHz, CDCl3): δ 8.19 (ddd, J = 2.1, 1.6, 0.5 Hz, 1H), 7.98 (ddd, J = 7.8, 1.6, 1.1 Hz, 1H), 7.69 (ddd, J = 8.0, 2.0, 1.1 Hz, 1H), 7.33 (ddd, J = 7.9, 7.9, 0.5 Hz, 1H), and 3.94 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 166.0, 136.1, 132.9, 132.3, 130.2, 128.4, 122.7, and 52.6; HRMS (ESI): Calcd for (M+H)+: 213.9629; Found m/z: 213.9677.
Iodide S2.1:
Preparation of Tetramethylpiperidine (TMP):
i) Hydrazine hydrate (59.6 mL, 64% purity, 1.227 mol) was added over to a triacetoneamine (117.5 g, 0.757 mol). The reaction mixture was warmed to 60 °C and stirred for 3.5 h.
ii) KOH (2.76 g, 0.0492 mol), diethylene glycol (14.6 mL), and paraffin oil (3.5 mL) were added to a 3-neck flask, which was assembled with 25 cm vigreux column and a distillation apparatus. The mixture was heated to ca. 210°C (±10 °C) and the hydrazone mixture was transferred via a cannula. Water was first distilled out and later TMP was distilled as a clear colorless oil (91.7 g, 85.8 %).
ii) TMP (36 mL, 212.8 mmol) was dissolved in THF (266 mL, 0.5 M) and n-BuLi (89.4 mL, 2.38 M, 212.8 mmol) was added to the solution at –20 °C. The reaction mixture was stirred for 30 min. The mixture was cooled to –78 °C and ester 2.11 (28.6 g, 133 mmol) in THF (60 mL) was added to the mixture via a syringe pump over 1.5 h, where the reaction mixture was stirred for 0.5 h. ZnCl2 [(266 mL, 1.0 M in Et2O), prepared through
drying in vacuo at 185 °C for 22 h and then dissolved in Et2O)] was added to the mixture
via a syringe pump over 0.5 h and was stirred for 0.5 h. I2 (54 g, 212.8 mmol) in THF (80
mL) was added over 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with Et2O. The combined organics were washed with brine, dried
over MgSO4, filtered and concentrated in vacuo. The resulting crude material was
purified via flash chromatography (10:1 = hex:EtOAc) or MPLC (7.5:1 = hex:EtOAc) to afford methyl 3-bromo-2-iodobenzoate S2.1 (43 g, 83%) as an inseparable mixture (7:1 = product:starting material), which was taken forward without further purification. 1H
Br I MeO
!
90!
NMR (500 MHz, CDCl3): δ 7.73 (dd, J = 8.0, 1.5 Hz, 1H), 7.45 (dd, J = 7.6, 1.6 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), and 3.94 (s, 1H); 13C NMR (125 MHz, CDCl
3): δ 167.9, 140.9, 134.8, 132.7, 129.3, 128.0, 101.0, 53.0. HRMS (ESI): Calcd for (M+H)+: 339.8596. Found m/z: 339.8615
Alcohol S.2:
The ester S2.1 (38.5 g, 113 mmol) was dissolved in THF (226 mL) and the solution was cooled to –78 °C. DIBAL-H (2.82 mL, 1.0 M in hexanes) was added to the solution over 1.5. The –78 °C bath was then replaced with a –20 °C ice/salt bath. After being stirred for 30 min at –20 °C, the reaction was first quenched with EtOAc and then half-saturated aqueous Rochelle salt. After being stirred for 2 h, the mixture was extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude solid material was triturated with hexanes. The resulting liquid was concentrated in vacuo and was purified by flash chromatography (8:1 to 4:1 = hex:EtOAc) affording the alcohol S2.2 (35 g, 99%) as a clear colorless oil. 1H NMR (500 MHz, CDCl3):
δ 7.58 (dddd, J = 7.9, 1.6, 0.6, 0.6 Hz, 1H), 7.38 (dddd, J =
7.6, 1.6, 0.8, 0.8 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 4.69 (d, J = 5.6 Hz, 2H), 2.34 (t, J = 5.9 Hz, 1H); 13C NMR (125 MHz, CDCl3):
δ 146.4, 131.9, 131.3, 129.7, 126.4, 104.3,
71.2; HRMS (CI+): Calcd for (M–OH)+: 294.8619. Found m/z: 294.8619. IR (thin film, neat): 3248 (br, m), 2917 (w), 1400 (m), 1051 (s) cm–1.
Br I
TBS ether 2.9:
The alcohol S2.2 (21.42 g, 68.45 mol), DMAP (418 mg, 3.423 mmol), and Et3N (19.06
mL, 136.9 mmol) were dissolved in CH2Cl2 (136.9 mL), and tert-Butyldimethylsilyl
chloride (11.86 mL, 78.72 mmol) was added to the solution. After being stirred for 2 h,
the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with
CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash chromatography (15:1 =
hex:EtOAc) amc afforded the silyl ether 2.9 (27.2 g, 93%) as a clear colorless oil. 1H
NMR (500 MHz, CDCl3): δ 7.56 (dddd, J = 7.9, 1.6, 0.8, 0.8 Hz, 1H), 7.47 (dddd, J = 7.7,
1.6, 1.0, 1.0 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 4.65 (dd, J = 1.0, 0.8 Hz, 2H), 1.01 (s, 9H),
0.18 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 146.8, 131.1, 130.6, 129.4, 125.6, 102.7,
71.4, 26.2, 18.6, –5.1; HRMS (ES+): Calcd for (M+H)+: 426.9590. Found m/z: 426.9581;
IR (thin film): 2954 (s), 2928 (s), 2883 (m), 2856 (s), 1256 (s), 1136 (s), 1105 (s) cm–1.
Ester 2.12:
Aryl iodide 2.9 (47.04 g, 110 mmol), PPh3 (5.77 g, 22 mmol) and Et3N (76.57 mL, 549
mmol) were sparged with argon for 30-40 min. Ethyl acrylate (23.91 mL, 219.9 mmol)
and Pd(OAc)2 (3.7 g, 16.49 mmol) were added to the mixture. The reaction vessel was
sealed with a Teflon®-lined cap and placed in a pre-heated oil bath at 85 °C for 8 h. The
Br I TBSO Br CO2Et TBSO
!
92!
reaction was stopped at ca. 82% conversion based on NMR. The crude material was
filtered through a pad of Celite®. The residue was purified by flash chromatography
(hexanes to 100:1 to 40:1 = hex:Et2O), affording the cinnamate ester 2.12 [32.43 g,
73.8% (brsm 90%)] and the starting material, aryl iodide 2.9 (7.1 g, 15% recovered SM)
as a clear colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.80 (d, J = 16.3 Hz, 1H), 7.54
(dd, J = 8.0, 1.3 Hz), 7.48 (dddd, J = 8.0, 1.3, 0.6, 0.6 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H),
6.28 (d, J = 16.3 Hz, 1H), 4.67 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H),
0.94 (s, 9H), 0.13 (s, 6H); 13C NMR (125 MHz, CDCl
3): δ 166.3, 141.9, 141.5, 134.2,
132.0, 129.8, 127.4, 125.9, 123.9, 63.6, 60.9, 26.0, 18.5, 14.5, –5.1; HRMS (CI+): Calcd
for (M+H)+: 399.1001. Found m/z: 399.0991; IR (thin film, neat): 2955 (s), 2929 (s), 2856
(s), 1722 (s), 1644 (m), 1179 (s) cm–1.
Allyl Alcohol S2.3:
The ester 2.12 (64.27 g, 160.9 mmol) was dissolved in THF (536.4 mL) and the resulting
mixture was cooled to –78 °C. DIBAL-H (482.8 mL, 1.0 M in hexanes, 482.8 mmol) was added and after being stirred for 1 h, the reaction mixture was first quenched with EtOAc and then half-saturated aqueous Rochelle’s salt. After being stirred for a further 2 h, the
mixture was extracted with Et2O. The combined organics were washed with brine, dried
over MgSO4 filtered and concentrated in vacuo. The residue was purified by flash
chromatography (10:1 = hex:EtOAc) affording allylic alcohol S2.3 (52.6 g, 91.5%) as a
clear colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.505 (dd, J = 7.9, 1.4 Hz, 1H), 7.493
(dd, J = 7.9, 1.4 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.61 (ddd, J = 16.2, 1.8, 1.8 Hz, 1H),
Br TBSO
6.03 (dt, J = 16.2, 5.3 Hz, 1H), 4.71 (s, 2H), 4.38 (ddd, J = 6.0, 5.3, 1.8 Hz, 2H), 1.53 (br s, 1H). 0.94 (s, 9H), 0.12 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 141.3, 136.0, 135.9,
131.3, 128.4, 127.2, 126.6, 123.9, 63.6, 63.4, 26.0, 18.5, –5.1; HRMS (CI+): Calcd for (M–OH)+: 339.0780. Found m/z: 339.0761; IR (thin film, neat): 3345 (br, m) 2953 (s), 2930 (s), 2857 (s), 1130 (s), 839 (s) cm–1.
Epoxy Alcohol (–)-2.13:
Molecular sieves (3Å, 310 mg) were placed in a round-bottom flask, which was flame- dried 3 times under vacuum. (–)-DIPT (45.86 g, 195.8 mmol) and CH2Cl2 (593 mL) were
added to the flask and the mixture was cooled to –45 °C. Ti(Oi-Pr)4 (46.23 mL, 156.61
mmol) was added to the mixture and the solution was stirred for 20 min. t-BuOOH (89 mL, 5 M in decane, 444.93 mmol; pre-treated with 4Å molecular sieves for 12 h) was added to the mixture, which was stirred for 40 min. at -45 °C. Allylic alcohol S2.3 (63.6
g, 177.97 mmol) in CH2Cl2 (119 mL) was added to the reaction mixture, which was
placed in a –30 °C freezer for 48 h. The reaction mixture was quenched with aqueous
citric acid (10%, 800 mL) at 0 °C and the resulting mixture was stirred for 40 min at 0 °C.
The aqueous layer was extracted with CH2Cl2. The combined organics were dried over
MgSO4, filtered and concentrated in vacuo. The residue was purified by flash
chromatography (hexanes to 10:1 = hex:EtOAc) affording the epoxy alcohol (–)-2.13 (62.99 g, 94.9%, 92% ee by SFC) as a clear colorless oil. 1H NMR (500 MHz, CDCl
3): δ 7.54 (dddd, J = 7.7, 1, 1, 1 Hz, 1H), 7.44 (dd, J = 8, 1 Hz, 1H), 7.19 (dd, J = 7.9, 7.9 Hz, 1H), 5.00 (d, J = 14.5 Hz, 1H), 4.94 (d, J = 14.5 Hz, 1H), 4.14 (ddd, J = 12.7, 5.1, 2.5 Hz, Br TBSO O OH
!
94!
1H), 3.99 (d, J = 2.2 Hz, 1H), 3.93 (ddd, J = 12.7, 7.8, 3.9 Hz, 1H), 3.22 (ddd, J = 3.9, 2.5, 2.5 Hz, 1H), 1.92 (dd, J = 7.8, 5.1 Hz, 1H), 0.96 (s, 9H), 0.13 (s, 3H), and 0.12 (s, 3H); 13C NMR (125 MHz, CDCl
3): δ 144.0, 132.4, 131.0, 129.5, 125.8, 122.9, 62.4, 61.4, 60.5, 55.8, 26.1, 18.6, –5.08, –5.14; HRMS (CI+): Calcd for (M+H)+: 373.0835. Found
m/z: 373.0810; IR (thin film, neat): 3404 (br, w), 2930 (m), 2857 (m), 1134 (m), 838 (s) cm–1; € α
[ ]
D 24 = –20.9 (c = 1.0, CHCl3). Carbamate S2.4:Preparation of benzoyl isocyanate:
Benzamide (46.35 g, 382.5 mol) and CH2Cl2 (765 mL) were added to a flask equipped with a reflux condenser. The heterogeneous mixture was stirred for 2 min and (COCl)2 (50.05 mL, 573.5 mmol) was added to the suspension at room temperature, which turned to a homogeneous clear solution. A drying tube was attached to the condenser and the reaction mixture was warmed to 85 °C for 18 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Excess (COCl)2 was removed via azeotropic evaporation with PhH (2X) and the resulting solid was dried under vacuum for 0.5 h.
The epoxy alcohol (–)-2.13 (60.36 g, 161.6 mmol) was dissolved in CH2Cl2 (648 mL) and the mixture was cooled to 0 °C. Benzoyl isocyanate (80.48 mL, 3.0 M in CH2Cl2) was added to the mixture at 0 °C, which was stirred for 30 min at 0 °C and warmed to rt.
Br TBSO O O N H O
After being stirred for 30 min, the reaction mixture was quenched with H2O (50 mL). The resulting mixture was extracted with CH2Cl2, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (5:1 to 3:1 = hex:EtOAc) affording the epoxy carbamate (–)-S.4 (78.1 g, 92.9%) as a clear colorless oil. 1H NMR (500 MHz, CDCl
3): δ 8.25 (s, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.60 (dddd, J = 8, 6.9, 1.3, 1.3 Hz, 1H), 7.55 (dddd, J = 7.8, 1.1, 1.1, 1.1 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.44 (dd, J = 8.0, 1.2 Hz, 1H), 7.21 (ddd, J = 7.9, 7.9, 0.5 Hz, 1H), 4.99-4.95 (m, 2H), 4.93 (dd, J =12.3, 2.4 Hz, 1H), 4.26 (dd, J = 12.4, 6.4 Hz, 1H), 3.96 (d, J = 2.3 Hz), 3.34 (ddd, J = 6.4, 2.3, 2.3 Hz, 1H), 0.96 (s, 9H), 0.130 (s, 3H), 0.128 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 164.9, 150.7, 144.0, 133.3, 133.0, 131.6, 131.0, 129.8, 129.1 (2), 127.8 (2), 125.9, 122.9, 66.0, 62.3, 57.5, 56.4, 26.1, 18.6, –5.10, –5.14; HRMS (ESI): Calcd for (M+H)+: 542.0974. Found m/z: 542.0953; IR (thin film, neat): 3285 (br, w), 2953 (m), 2849 (m), 1763 (s), 1693 (w), 1518 (s), 1194 (s) cm–1; € α
[ ]
D 24 = –8.47 (c = 0.353, CHCl3). Oxazolidinone (+)-2.8:The epoxy carbamate (–)-S2.4 (72.6 g, 139.48 mmol) was dissolved in CH2Cl2 (558 mL), then H2O (558 mL) was added. Bu4NCl (11.63 g, 41.844 mmol) and K2CO3 (38.56 g, 278.96 mmol) were added to the solution. The reaction vessel was closed with a Teflon®-lined cap and vigorously stirred for 71 h. The mixture was diluted with H
2O, and Br TBSO BzO N O O H
!
96!
the resulting mixture was extracted with CH2Cl2. The combined organics were washed
with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was
purified by flash chromatography (6:1 to 4:1 = hex:EtOAc) affording oxazolidinone (+)- 2.8 (67.9 g, 93.5%) as a clear colorless oil. 1H NMR (500 MHz, CDCl
3): δ 8.061 (d, J = 8.3 Hz, 1H), 8.058 (d, J = 8.4 Hz, 1H), 7.60 (dddd, J = 7.8, 7.0, 1.3, 1.3 Hz, 1H), 7.56 (dd, J = 8, 1.3 Hz, 1H), 7.53 (dd, J = 7.8, 1.3 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.22 (dd, J = 7.9, 7.9 Hz, 1H), 4.64 (s, 1H), 5.13, (d, J = 13.2 Hz, 1H), 4.97 (s, 1H), 4.89 (m, 1H), 4.64 (dd, J = 9.2, 7.9 Hz, 1H), 4.47 (dd, J = 9.2, 4.6 Hz, 1H), 0.95 (s, 9), 0.15 (s, 3H), 0.13 (s, 3H); 13C NMR (125 MHz, CDCl 3): δ 165.4, 158.5, 133.9, 132.3, 131.6, 130.7, 130.1 (2), 129.08, 129.02, 128.9 (3), 123.8, 68.7, 63.9, 63.0, 54.0, 26.1, 18.6, –5.08, –5.1; HRMS (ESI/TOF): Calcd for (M+H)+: 542.0974. Found m/z:
542.1001; IR (thin film, neat): 3253 (br, w), 2954 (m), 2928 (m), 1763 (s), 1727 (s), 1263 (br, s) cm-1; € α
[ ]
D 24 = +41.9 (c = 4.73, CDCl3). Indoline S2.5:Note: The purity of the starting material (+)-2.8 is critical.
To a round bottomed flask containing flame-dried (3x) Cs2CO3 (124.98 g, 383.58 mmol),
P(o-tol)3 (62.26 g, 20.45 mmol), Pd2(dba)3 (5.88 g, 10.23 mmol), and aryl bromide (+)-
2.8 (66.55 g, 127.86 mmol) were added. The mixture was dissolved in PhMe (639 mL, 0.2 M; degassed by purging with argon for 20 minutes prior to use) and the reaction
TBSO
N O BzO
vessel was closed with a Teflon®-lined cap and heated to 90
°C for 1.5 h. After being
cooled back to room temperature, the crude reaction mixture was filtered through Celite with EtOAc and the filtrate was concentrated. The residue was purified by flash chromatography (7:1 to 5:1 = hex:Et2O) affording indoline (+)-S2.5 (52 g, 92.5%), contaminated with dibenzylideneacetone (dba). The impure indoline (51.8 g, 117.84 mmol) and CeCl3 (8.78 g, 23.57 mmol) were dissolved in MeOH (29.5 mL) and THF (58.9 mL). The resulting solution was cooled to 0 °C. NaBH4 (1.27 g, 47.14 mmol) was added to the solution. The resulting mixture was filtered through a plug of Celite washed with MeOH and EtOAc. The mixture was concentrated in vacuo and solidified upon treatment with hexanes, which was filtered to yield the pure indoline (+)-S2.5. The filtrate was concentrated in vacuo and purified with flash chromatography (10:1 hex:EtOAc) to afford the indoline (+)-S105 (combined yield, 44 g, 78.6%). 1H NMR (500 MHz, CDCl3): δ 8.063 (d, J = 8.2 Hz, 1H), 8.061 (d, J = 8.4 Hz, 1H), 7.64 (dddd, J = 7.8, 7.0, 1.3, 1.3 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.484 (d, J = 8.3 Hz, 1H), 7.478 (d, J = 7.9 Hz, 1H), 7.44 (dd, J = 7.8, 7.8 Hz, 1H), 7.29 (dddd, J = 7.4, 1, 1, 1 Hz, 1H), 6.31 (d, J = 5.8 Hz, 1H), 4.95, (ddd, J = 13.6, 8.3, 5.8 Hz), 4.89 (d, J = 13.5 Hz, 1H), 4.84 (d, J = 13.5 Hz, 1H), 4.64 (dd, J = 13.6, 8.6 Hz, 1H), 4.47 (dd, J = 8.6, 5.8 Hz, 1H), 0.88 (s, 9H), 0.37 (s, 3H), and 0.006 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 167.4, 156.4, 141.6, 140.3, 134.2, 131.4, 130.0, 129.1 (2), 129.0 (2), 126.1, 123.6, 114.9, 82.2, 70.1, 67.5, 62.7, 26.1, 25.9, 18.6, –5.2, –5.3; HRMS (ESI): Calcd for (M+Na)+: 462.1713. Found:
m/z: 462.1720; IR (thin film, neat): 2928 (m), 1771 (s), 1717 (s), 1266 (s), and 1109 (s) cm–1; € α
[ ]
D 24 = +107.1° (c = 1.0, CDCl3).!
98!
Alcohol S2.6:
Benzoate (+)-S2.5 (43.3 g, 98.5 mmol) was dissolved in THF (3940 mL) and the mixture was cooled to –78 °C. MeLi (147.8 mL, 1.6 M in ether, 236.4 mmol) was added in a dropwise manner. The reaction was monitored by TLC and upon consumption of the starting material, the reaction mixture was quenched with EtOAc and pH 7 buffer. The resulting mixture was extracted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (5:1 to 2:1 = hex:EtOAc) affording alcohol (–)-S.6 (26.55 g, 81.2%) as a clear colorless oil. 1H NMR (500 MHz, CDCl 3): δ 7.44 (dd, J = 7.9, 1.0 Hz, 1H), 7.30 (dd, J = 7.8, 7.8 Hz, 1H), 6.96 (dddd, J = 7.6, 1.0, 0.7, 0.7 Hz, 1H), 5.59 (d, J = 6.2 Hz, 1H), 4.89 (d, J = 12.9 Hz, 1H), 4.84 (dd, J = 8.9, 8.9 Hz, 1H), 4.78 (d, J = 12.9 Hz, 1H), 4.69 (ddd, J = 8.8, 8.0, 6.2 Hz, 1H), 4.37 (dd, J = 9.0, 8.0 Hz, 1H), 0.93 (s, 9H), 0.18 (s, 3H), and 0.14 (s, 3H); 13C NMR (125 MHz, CDCl 3): δ 156.6, 141.4, 137.7, 133.7, 130.2, 124.0, 115.7, 78.6, 69.4, 67.6, 65.3, 26.0, 18.4, –5.1; HRMS (ESI/TOF): Calcd for (M+Na)+: 358.1445. Found m/z: 358.1465; IR (thin film, neat): 3415 (br, m), 2954 (m), 2929 (m), 1747 (s), 1460 (s), 837 (s) cm–1; € α
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D 24 = –53.8° (c = 2.0, CDCl3). TBSO N O HO OTIPS ether (+)-2.35:
The alcohol (–)-S2.6 (27.2 g, 81.08 mmol) and 2,6-lutidine (28.3 mL, 243.2 mmol) were dissolved in CH2Cl2 (162 mL) and the solution was cooled to 0 °C. TIPSOTf (32.7 mL, 121.6 mmol) was added to the mixture, which was subsequently warmed to rt. After being stirred for 48 h, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (15:1 to 13:1 = hex:EtOAc) affording the silyl ether (+)-2.35 (39 g, 97.8%) as a clear colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.37 (br s, 3H), 5.77 (d, J = 5.9 Hz, 1H), 4.99 (d, J = 14.4 Hz, 1H), 4.85 (d, J = 14.4 Hz, 1H), 4.79 (dd, J = 8.8, 8.8 Hz, 1H), 4.65 (ddd, J = 8.6, 8.6, 5.9 Hz, 1H’), 4.35 (dd, J = 8.7, 8.7 Hz, 1H), 1.17-1.10 (m, 21H), 0.96 (s, 9H), and 0.11 (s, 6H); 13C NMR (126 MHz, CDCl3): δ 155.98, 140.62 (2), 139.71, 130.29, 130.27, 122.70, 113.91, 80.59, 69.22, 68.45, 61.81, 26.11, 18.59, 18.42, 18.35, 13.20, –5.11; HRMS (ESI): Calcd for (M+Na)+: 514.2779. Found m/z: 514.2795. IR (thin film, neat): 3410 (br w), 2947 (m), 2863 (m), 1777 (s), 1599 (w), 1459 (s), 1390 (m), 1106 (m),836 (s) cm–1; € α
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D 24 = +0.47° (c = 2.32, CHCl3). TBSO N O TIPSO O!
100!
Iodide 2.35:Indoline (+)-2.34 (50 mg, 0.102 mmol) was dissolved in 0.5 mL of CH3CN and 0.5 mL of CH2Cl2. AgNO3 (26 mg, 0.152 mmol) followed by I2 (39 mg, 0.152 mmol) were then added to generate an orange suspension. The reaction mixture was stirred for 5 h at rt, before the reaction mixture was quenched with saturated aqueous Na2S2O3 and extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (6:1 to 3:1 = hex:EtOAc) affording the iodide (+)-2.35 (41 mg, 65%) as an off-white semisolid. 1H NMR (500 MHz, CDCl 3): δ 7.82 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 5.94 (d, J = 4.6 Hz, 1H), 5.21 (d, J = 11.7 Hz, 1H), 4.81 (t, J = 8.8 Hz, 1H), 4.71 (d, J = 11.7 Hz, 1H), 4.64 (ddd, J = 9.4, 8.7, 4.7 Hz, 1H), 4.26 (t, J = 9.2 Hz, 1H), 1.12-1.11 (m, 21H), 0.88 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H), 0.08 (s, 6H); 13C NMR (126 MHz, CDCl3): δ 156.32, 141.57, 141.48, 134.64, 116.64, 94.66, 79.25, 69.36, 68.20, 65.99, 26.11, 18.47, 18.36, 18.31, 17.85, 13.21, 1.17, -4.25, -4.52; HRMS (ESI): Not Determined IR: Not Determined;
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D 24 = Not Determined TBSO N O O TIPSO IBenzylic Alcohol S2.7:
TBS ether 2.35 (40 mg, 0.065 mmol) was dissolved in 0.6 mL of EtOH and 0.15 mL of CH2Cl2. Camphorsulphonic acid (8 mg, 0.032 mmol) was added to the mixture and the reaction mixture was stirred for 24 h at rt. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (6:1 = hex:EtOAc) affording 29 mg S.7 (91 %) as a yellow waxy solid. 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 5.92 (d, J = 5.8 Hz, 1H, 4.87 (d, J = 11.8 Hz, 1H), 4.74 (dd, J = 8.5, 8.5 Hz, 1H), 4.74 (d, J = 11.8 Hz, 1H), 4.62 (ddd, J = 8.5, 8.5, 5.9 Hz, 1H), 4.33 (dd, J = 8.7, 8.7 Hz, 1H), 2.53 (bs, 1H), 1.20-1.10 (m, 21H); 13C NMR (125 MHz, CDCl3): δ 155.54, 141.39, 141.21, 140.85, 134.54, 116.79, 95.14, 80.61, 69.11, 67.83, 65.31, 18.25, 18.15, 13.08; HRMS (ESI): Calcd for (M+H)+: 504.1062. Found m/z: 504.1064. IR (thin film, neat): 3462 (br w), 2946 (m), 2867 (m), 1768 (s), 1647 (w), 1587 (w), 1477 (s), 1101 (s), 818 (s) cm–1; € α
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D 24 = +19.5° (c = 1.67, CDCl3). HO N O O TIPSO I!
102!
Aldehyde (+)-2.36: The benzyl alcohol SS.7 (29 mg, 0.058 mmol) was dissolved in 1.15 mL CH2Cl2. NaHCO3 (10 mg, 0.115 mmol) and DMP (49 mg, 0.115 mmol) were added to the solution. After being stirred for 30 min, the reaction mixture was diluted with saturated aqueous NaHCO3 and CH2Cl2 . The aqueous layer was extracted with CH2Cl2 (3x) and the combined organics were dried over MgSO4, then filtered and concentrated
in vacuo. The residue was purified by flash chromatography (6:1 to 3:1 = hex:EtOAc) affording 29 mg of (+)-2.36 (99 %) as a waxy yellow solid. 1H NMR (500 MHz, CDCl3): δ 10.09 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.08 (d, J = 4.7 Hz, 1H), 4.78 (dd, J = 8.8, 8.8 Hz, 1H), 4.64 (ddd, J = 9.1, 8.8, 4.7 Hz, 1H), 4.32 (dd, J = 9.1, 9.1 Hz, 1H), and 1.16-1.01 (m, 21H); 13C NMR (125 MHz, CDCl3): δ 194.61, 156.08, 142.55, 142.28, 136.91, 133.57, 121.16, 91.38, 78.02, 69.22, 68.73, 18.28, 18.26, and 12.78; HRMS (ESI): Calcd for (M+Na)+: 524.0724. Found m/z: 524.0722; IR (thin film, neat): 3400 (br w), 2943 (m), 2865 (m), 1776 (s), 1700 (m), 1583 (w), 1447 (m), 1115 (m), and 822 (m) cm–1; € α
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D 24 = +31° (c = 0.085, CDCl3). N O TIPSO O I O HHydrazone (+)-2.37:
Note: The purity of the starting materials, (+)-2.36 and (+)-2.6 is critical to achieve higher dr and yield.
Hydrazone (+)-2.6 (0.502 g, 68.58 mmol) was dissolved in THF (685.8 mL, 0.1 M) and the solution was cooled to –78 °C. t-BuLi (46.56 mL, 1.473 M in hexanes, 68.58 mmol) was added to the solution at –78 °C. After being stirred for 1 h at -78 °C, the reaction
mixture was cooled to –100 °C (liquid N2/EtOH bath). Sc(OTf)3 (1.87 g, 3.81 mmol) was
added to the aza-enolate solution, and the pre-cooled aldehyde (+)-2.36 (29.3 g, 38.1 mmol, 1 equiv) in THF (165 mL, 0.23 M) at –78 °C was added to the reaction mixture via a cannular dropwise. After being stirred for 1 h at –100 °C, the reaction mixture was
warmed to –78 °C and stirred for additional 1 h. The mixture was quenched with pH 7
buffer at –78 °C and the solution was slowly warmed to rt. The resultant mixture was extracted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated in
vacuo. The residue was purified by flash chromatography (3:1, then 1:1 = hex:EtOAc) affording hydrazone (+)-2.37 (19.412 g, 66.3%, 6.5:1 dr) and recovered the aldehyde (+)-2.36 (2.852 g, 14.9%). 1H NMR (500 MHz, CDCl3, 320K): δ 7.88 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 4.0 Hz, 1H), 5.51 (dd, J = 8.8, 8.8 Hz, 1H), 4.97 (d, J = 8.8 Hz, 1H), 4.80 (dd, J = 8.6, 8.6 Hz, 1H), 4.69 (ddd, J = 9.1, 8.6, 4.4 Hz, 1H), 4.32 (dd, J = 9.1, 8.6 Hz, 1H), 3.54 (d, J = 8.8 Hz, 1H), 3.25-3.14 (m, 1H), 3.20 (s, 3H), 3.07 (d, J = 13.0 Hz, 1H), 3.08-3.00 (m, 1H), 2.87-2.80 (m, 1H), 2.60-2.51 (m, 1H), 2.59-2.53 N O TIPSO O I OH O N N MeO H
!
104!
(ddd, J = 8.8, 9.0, 9.2 Hz, 1H), 2.15 (d, J = 13.0 Hz, 1H), 2.09-2.01 (m, 1H), 1.90-1.81 (m, 1H), 1.78-1.71 (m, 1H), 1.65 (s, 3H), 1.45 (s, 3H), 1.38-1.33 (m, 1H), 1.16 (s, 6H), 1.16-1.10 (m, 21H); 13C NMR (125 MHz, CDCl 3): δ 162.5, 155.61, 144.29, 142.68, 142.51, 132.86, 116.60, 80.90, 78.86, 77.57, 75.42, 75.33, 69.03, 68.08, 66.62, 59.09, 55.59, 54.00, 44.73, 34.07, 32.07, 29.81, 28.76, 27.35, 22.47, 18.39, 18.31, and 14.07; HRMS (ESI): Calcd for (M+H)+: 770.3056. Found m/z: 770.3062; IR (thin film, neat): 3395 (br m), 2948 (m), 2869 (m), 1779 (s), 1637 (m), 1570 (w), 1442 (m), 1101 (m), 730 (m) cm–1; MP: 159-160 °C; € α[ ]
D 24 = +114° (c = 1.31, CDCl3) Enone (+)-3.32:In a round bottom flask, 4 Å molecular sieves (50 g) were activated by flame drying under vacuum. Ketone (+)-3.5 (100 g, 560 mmol) was dissolved in ethylene glycol (1.8 L). p-Toluenesulfonic Acid monohydrate (106.5 g, 560 mmol) was then added and the solution was stirred for 16 hours. The reaction was poured into NaHCO3 and ice, then the solids were filtered through Celite and the filter cake was washed with EtOAc. The aqueous fraction was then extracted with EtOAc. The combined organics were then dried over MgSO4 and concentrated in vacuo. The crude mixture was filtered through a plug of silica gel with 2:1 (hex:EtOAc) and concentrated to give 107.3 g (82 %) of (+)- 3.32 as an oil. 1H NMR (500 MHz, CDCl3): δ 4.02-3.91 (m, 4H), 2.77-2.72 (m, 1H), 2.51-2.37 (m, 2H), 2.28-2.21 (m, 1H), 2.16 (dddd, J = 15.3, 13.7, 5.6, 1.5 Hz, 1H), 1.90 (td, J = 13.4, 4.6 Hz, 1H), 1.84-1.81 (m, 1H), 1.79 (d, J = 1.5 Hz, 3H), 1.72-1.61 (m, 3H), O Me O O Me
1.34 (d, J = 0.6 Hz, 3H); 13C NMR (125 MHz, CDCl
3): δ 198.82, 160.23, 130.31, 112.93,
65.49, 65.22, 45.44, 33.85, 29.88, 26.66, 26.61, 21.58, 21.02, 11.63.
Alcohol (+)-3.33:
A 500 mL 3-neck round bottom flask equipped with a cold finger was cooled to –78 °C. Then, ammonia gaswas condensed into the flask (325 mL) and lithium metal (1.26 g,